This document discusses magnesium disorders and hypomagnesemia. It begins by providing background on magnesium, including where it is stored in the body and its many functions. It then discusses the causes, clinical manifestations, diagnosis, and treatment of hypomagnesemia. Hypomagnesemia can be caused by renal magnesium wasting due to drugs, diseases, or genetic disorders, or by extrarenal losses from poor nutrition, malabsorption, diarrhea, or sweat losses. Symptoms affect the cardiovascular, neuromuscular, skeletal, and central nervous systems. Treatment involves identifying and addressing the underlying cause, as well as oral or parenteral magnesium supplementation.

1. Magnesium
Disorders

2. Introduction
 Magnesium – one of the most abundant ions in the
body
 Bone – 50-60% (reservoir for maintaining extracellular
and intracellular Mg)
 Circulation - <1%
 Most intracellular Mg –found in - nucleus,
mitochondria, endoplasmic/sarcoplasmic reticulum,
and the cytoplasm.
 The majority is bound to adenosine triphosphate (ATP).
 Involved in over 300 enzymatic reactions
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3. Introduction
 2nd most abundant intracellular ion
 Total body content = 2000 mEq
 Intracellular concentration = 40 mEq/dl
 Serum concentration is between 1.5 and 2.3 mg/dl
 Total Mg = Ionised and bound (ATP and others)
 Ionised Magnesium ~70% of total
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4. Introduction
Dietary sources
 Nuts
 Dried peas and beans
 Whole grain cereals (oatmeal, millet, brown rice)
 Dark green vegetables
 Soy products
Most dietary absorption occurs in the ileum and jejunum
(upto 65%)
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5. Renal handling of Magnesium
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6. Hypomagnesemia
 Surveys of serum Mg levels in hospitalized patients
indicate a high incidence of hypomagnesemia
 Ranges between 11% - 60%
 Patients with hypomagnesemia had increased
mortality compared with normomagnesemic patients
 Serum magnesium levels do not correlate well with
body magnesium stores
Hypomagnesemia
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7. Etiology of Hypomagnesemia
Hypomagnesemia
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8.  When the cause is undetermined from the history and
physical examination alone –
 Helpful to distinguish between renal Mg2+ wasting and
extrarenal causes of Mg deficiency
 By assessing urinary Mg excretion.
 24 hr urine magnesium
 Fractional excretion of Magnesium (FEMg)
 A urine Mg excretion rate greater than 24 mg/day
suggests renal Mg wasting
Etiology of Hypomagnesemia
Hypomagnesemia
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9.  Fractional excretion of Magnesium – calculated by
 The factor of 0.7 is applied - to estimate free Mg2+
 FEMg of more than 2% in an individual with normal
GFR - indicates inappropriate urinary Mg loss
 If no renal wasting – extrarenal loss to be considered
Etiology of Hypomagnesemia
Hypomagnesemia
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10. Renal Magnesium Wasting
1. Polyuria
 Osmotic diuresis
 Diabetic ketoacidosis
 Polyuric phase of recovery from acute renal failure
 Recovery from ischemic injury in a transplanted kidney
 Postobstructive diuresis
Hypomagnesemia
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11. Renal Magnesium Wasting
2. Extracellular Fluid Volume Expansion
 Mg reabsorption is passive and is driven by the
reabsorption of sodium and water in the PCT
 Extracellular volume expansion - decreases proximal
sodium and water reabsorption – hence reducing
magnesium reabsorbtion
3. Diuretics
 Loop diuretics’ inhibition of the NaK2Cl co transporter
abolish the transepithelial potential difference
 as a result, magnesium resorption is inhibited
 Hypomagnesemia is a frequent finding in patients
receiving long-term loop diuretic therapy
Hypomagnesemia
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12. Renal Magnesium Wasting
3. Diuretics
 Long-term treatment with thiazide diuretics, which inhibit
the NaCl cotransporter (DCT) also cause renal Mg
wasting
 Thiazides downregulate the expression of TRPM6
 may explain the mechanism of the magnesuria
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13. Renal Magnesium Wasting
4. Epidermal Growth Factor Receptor Blockers
 Hypomagnesemia is common in patients receiving
cetuximab and panitumumab
 Used in treating metastatic colorectal carcinoma
 Almost 50% in patients treated for longer than 6 months
develop hypomagnesemia (reverses 1 - 3 months after
discontinuation)
 FEMg is inappropriately elevated
 Recent studies suggest that the EGF receptor is located
basolaterally in the DCT - redistribution of TRPM6 to the
apical membrane – mediating Mg absorption
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14. Renal Magnesium Wasting
CETUXIMAB
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15. Renal Magnesium Wasting
5. Hypercalcemia
 Elevated serum ionized Ca levels (malignant bone
metastases) directly induce renal Mg wasting
 Inhibits magnesium reabsorption
 However, in hyperparathyroidism – PTH stimulates Mg
resorption – Thus normal levels maintained
Hypomagnesemia
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16. Renal Magnesium Wasting
6. Drugs
i. Cisplatin
 Hypomagnesemia is almost universal at a monthly
dose of 50 mg/m2
 Suggested that the reabsorption defect may be in
the DCT
 Occurrence of Mg wasting does not correlate with
cisplatin-induced acute renal failure
 Magnesuria usually stops by 5 months (may be life
long)
 Carboplatin – considerably less magnesuria and
renal failure
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17. Renal Magnesium Wasting
6. Drugs
ii. Amphotercin B
 Causes dose dependent renal Mg wasting and
hypomagnesemia
 Suggested that the functional tubule defect resides
in the DCT
 Other manifestations - hypokalemia, distal renal
tubular acidosis, acute renal failure with tubule
necrosis, nephrocalcinosis
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18. Renal Magnesium Wasting
6. Drugs
iii. Aminoglycosides
 Cause a syndrome of renal Mg and K wasting with
hypomagnesemia, hypokalemia, hypocalcemia,
and tetany
 Hypomagnesemia may occur despite levels in the
appropriate therapeutic range
 it is the cumulative dose of aminoglycoside that is the
key predictor of toxicity (>8g)
 No correlation between the occurrence of
aminoglycoside-induced ATN and
hypomagnesemia.
 Hypomagnesemia occurs ~ 3 - 4 days after the start
of therapy and readily reverses after cessation of
therapy.
Hypomagnesemia
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19. Renal Magnesium Wasting
6. Drugs
iv. Others
 The calcineurin inhibitors cause hypomagnesemia in
renal transplant patients - downregulation of the Mg
channel TRPM6
 Pentamidine & foscarnet-induced hypomagnesemia
- associated with significant hypocalcemia.
Hypomagnesemia
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20. Renal Magnesium Wasting
7. Inherited Renal Magnesium-Wasting Disorders
i. Bartter’s syndrome
 Autosomal recessive disorder
 Sodium wasting, hypokalemic metabolic alkalosis, and
hypercalciuria, and usually occurs in infancy or early
childhood
 30-35% have hypomagnesemia *
 Physiology of bartter’s syndrome - identical to that of
long-term loop diuretic therapy
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21. Renal Magnesium Wasting
7. Inherited Renal Magnesium-Wasting Disorders
ii. Gitelman’s syndrome
 Variant of Bartter’s syndrome - distinguished primarily by
hypocalciuria
 usually > 6 yrs, mild symptoms
 inactivating mutations in the DCT - thiazide-sensitive NaCl
cotransporter (NCC)
 Hypomagnesemia occurs in 100%
 Resembles the effects of long-term thiazide diuretic
therapy
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22. Renal Magnesium Wasting
7. Inherited Renal Magnesium-Wasting Disorders
iii. Familial hypercalciuric hypomagnesemia with
nephrocalcinosis
 FHHNC is a rare autosomal recessive tubular disorder
 The primary defect - impaired tubular reabsorption of
magnesium and calcium in the thick ascending limb
iv. Familial Hypomagnesemia with Secondary
Hypocalcemia (HSH)
 Rare autosomal recessive
 Mutations in TRPM6 gene
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23. Extrarenal Causes
1. Nutritional Deficiency
 Severe dietary insufficiency is extremely difficult - nearly
all foods contain significant amounts of Mg and renal
adaptation to conserve Mg is very efficient
 Mean daily intake estimated at 323 mg in males and 228
mg in females (RDA - 420 mg for males and 320 mg for
females)
 Mg deficiency of nutritional origin occurs particularly in
two clinical settings: alcoholism and parenteral feeding
 20% to 25% of alcoholic patients are hypomagnesemic
 Parenteral – Sick patients with ongoing salt loss and other
electrolyte imbalances
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24. Extrarenal Causes
2. Intestinal Malabsorption & Diarrhea
 Generalized malabsorption syndromes (Celiac disease,
Whipple’s disease, IBD) – associated with intestinal Mg
wasting and Mg deficiency
 In fat malabsorption (steatorrhea) – the fatty acids in the
stools combine with magnesium to form non-absorbable
soaps (saponification)
 Mg deficiency was a common complication of bariatric
surgery by jejunoileal bypass
 proton pump inhibitors have been reported to cause
hypomagnesemia in some patients, the evidence
suggests toward intestinal Mg malabsorption
 The Mg concentration of diarrheal fluid ranges from 1-16
mg/dL – Chronic diarrhea(± malabsorption)
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25. Extrarenal Causes
3. Cutaneous Losses
 Sweat contains up to 0.5 mg/dL of Mg.
 Prolonged intense exertion can result in a Serum Mg fall
of 20%
 Hypomagnesemia occurs in 40% of patients with severe
burn injuries
4. Redistribution to Bone Compartment
 Hypomagnesemia may accompany profound
hypocalcemia of hungry bone syndrome in
hyperparathyroidism
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26. Clinical Manifestations
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 Hypomagnesemia may cause symptoms and signs of
disordered functions of
 Cardiovascular system
 Neuromuscular system
 Central nervous system
 Skeletal System
 Associated with an imbalance of other electrolytes
such as potassium and calcium*

27. Clinical Manifestations
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Cardiovascular System
 Mg is an obligate cofactor in all reactions that require
ATP (includes Na-K-ATPase)
 In hypomagnesemia, Impaired Na- K-ATPase
function fall in intracellular K+ depolarized resting
membrane potentialpredisposes to ectopic
excitation and tachyarrhythmias
 ECG changes - bifid T waves, U waves, QT
prolongation
 Also, hypomagnesemia facilitates the development of
digoxin cardiotoxicity (additive effects on Na- K-ATPase)

28. Clinical Manifestations
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Cardiovascular System
 One study - Low dietary Mg level appeared to
increase the risk for supraventricular and ventricular
ectopy despite absence of frank hypomagnesemia,
hypokalemia, and hypocalcemia
 Framingham Offspring Study - lower levels of serum Mg
were associated with higher prevalence of ventricular
premature complexes
 Also, Mg treatment was associated with an
approximately 25% lower mortality in Acute MI in one
study (LIMIT-2)
 Recent studies show no difference in mortality

29. Clinical Manifestations
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Cardiovascular System
 Mg deficiency is associated with systemic
hypertension
 Mechanism is not clear, however - Mg does regulates
vascular tone and reactivity and attenuates agonist-
induced vasoconstriction

30. Clinical Manifestations
Hypomagnesemia
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Neuromuscular System
 Symptoms and signs of neuromuscular irritability,
including tremor, muscle twitching, Trousseau’s and
Chvostek’s signs and frank tetany, may develop in
patients with isolated hypomagnesemia
 Seizures - generalized and tonic-clonic or multifocal
motor seizures (noise induced)
 The effects of Mg deficiency – mediated by N-methyl-
D-aspartate (NMDA)–type glutamate receptors –
excitatory receptors in the brain

31. Clinical Manifestations
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Neuromuscular System
 Extracellular Mg normally blocks NMDA receptors, Mg
deficiency releases the inhibition

32. Clinical Manifestations
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Neuromuscular System
 Hypocalcemia is often observed in Mg deficiency and
may also contribute to the neuromuscular
hyperexcitability
 Vertical nystagmus is a rare but diagnostically useful
neurologic sign of severe hypomagnesemia
 Only recognized metabolic causes of vertical
nystagmus are Wernicke’s encephalopathy and
severe Mg deficiency*

33. Clinical Manifestations
Hypomagnesemia
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Skeletal System
 Hypomagnesemia - decreased skeletal growth and
increased fragility
 Mg is mitogenic for bone cell growth, deficiency may
directly result in a decrease in bone formation
 It also affects crystal formation; Mg deficiency results in
a larger, more perfect crystal (which is brittle)
 Mg deficiency may result in a fall in both serum PTH
and Vitamin D levels

34. Clinical Manifestations
Hypomagnesemia
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Electrolyte Homeostasis
 Patients with hypomagnesemia are frequently also
hypokalemic
 Hypomagnesemia by itself can induce hypokalemia*
(release of inhibition of ROMK channels)
 The cause of the hypokalemia is increased secretion in
the distal nephron
 Hypocalcemia occurs in ~50% pts - impairment of PTH
secretion by Mg deficiency

35. Clinical Manifestations
Hypomagnesemia
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Others
 Hypomagnesemia worsens insulin resistance and also
accelerates progression of nephropathy and
retinopathy in diabetics
 Mg deficiency has been associated with migraine
headache
 Some evidence in Mg deficiency resulting in smooth
muscle spasm and has been implicated in asthma
 Finally, a high dietary Mg intake has been associated
with reduced risk of colon cancer

36. Treatment
 Identifying and treating the cause where possible
 Oral bioavailability is ~33% (Normal intestine)
 In mild deficiency states and symptomatic illness –
about 800 mg of Magnesium oxide/hydroxide in 4-5
divided doses or 3 g of Magnesium sulphate in 4
divided doses
 Parenteral administration for inpatients (IM/IV)
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37. Treatment
IM admin
 For mild deficiency: 1 g every 6 hr for 4 doses or based
on serum magnesium levels.
 For severe deficiency: up to 250 mg/kg within a 4-hr
period if needed
IV admin:
 For symptomatic deficiency: 1-2 g over 5-60 minutes
followed by maintenance infusion at 0.5-1 g/hr to
correct the deficiency.
 For severe hypomagnesemia: 1-2 g/hr for 3-6 hr, then
0.5-1 g/hr as needed based on serum magnesium
levels.
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38. Treatment
 A simple regimen would be 8g of MgSO4 over the first
24 hours and then 4g daily for the next 2 to 6 days
 Serum Mg levels rise early, whereas intracellular stores
take longer to replenish (correction to continue for
atleast 2 days after normalization of levels)
 Toxicity - facial flushing, loss of deep tendon reflexes,
hypotension and atrioventricular block
 Administration of MgSO4 may further lower the
ionized Ca2+ level and thereby precipitate tetany
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39. Treatment
Potassium sparing (ENaC blocker) diuretics
 Distal tubule epithelial Na channel, such as amiloride
and triamterene, may reduce renal Mg losses
 Useful in patients refractory to oral replacement or
patients not tolerating high Mg doses (diarrhea)
Hypomagnesemia
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40. Hypermagnesemia
 The kidney has a very large capacity for Mg excretion
 Once the renal threshold is exceeded, most of the
excess filtered Mg is excreted unchanged into urine
 After this point, serum Mg is determined by GFR
 Thus Hypermagnesemia occurs only in
1. Renal insufficiency
2. Excessive intake/correction
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41. Causes
Renal insufficiency
• In CKD –the remaining nephrons adapt to the decreased
filtered load of Mg by markedly increasing their fractional
excretion of Mg
• This mechanism is compromised as renal failure worsens
(especially when on Mg containing formulations)
Excessive Magnesium intake
• Therapeutic overdose (IV/Oral/Antacids/Enemas)
Others
• Lithum therapy, bone metastases, hypothyroidism –
associated with hypermagnesemia
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42. Clinical manifestations
 Mg toxicity is a serious and potentially fatal condition.
 Initial manifestations( S. Mg > 4 mg/dL) are
hypotension, nausea, vomiting, facial flushing, urinary
retention and ileus.
 If untreated, Mg toxicity (S. Mg 8 to 12 mg/dL) may
progress to
• Flaccid skeletal muscular paralysis and hyporeflexia
• Bradycardia and bradyarrhythmias
• Respiratory depression
• Coma
• Cardiac arrest.
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43. Treatment
 Mild toxicity with good renal function – cessation of
Mg supplements (half life of Mg is 28 hrs)
 Severe toxicity (particularly cardiac) – Calcium can
antagonize magnesium
 IV Calcium Chloride 1g over 2-5 minutes, repeated after
5 min if necessary
 Saline diuresis and administration of furosemidecan
increase excretion
 Dialysis – Very effective - Mg free dialysate (causes
muscle cramps)
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44. Hypomagnesemia
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45. Hypomagnesemia
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